Nicotinic acid derivatives

ABSTRACT

6 - HALO-2-HYDROXYNICOTINIC ACID, 4-AMINO-2-HYDROXYNICOTINIC ACID, 2-HYDROXY-4-(LOWER ALKYL)NICOTINIC ACID, 2HYDROXY-5-(LOWER ALKYL)NICOTINIC ACID, 5-HALO-2-HYDROXYNICOTINIC ACID, AND THEIR SALTS, USEFUL AS HYPOLIPIDEMIC AGENTS, ARE DESCRIBED.

United States Patent 3,738,990 NICOTINIC ACID DERIVATIVES Alden GamalielBeaman, North Caldwell, and Oscar Neal Miller, Montclair, N.J.,assignors to Holfmann-La Roche Inc., Nutley, NJ. No Drawing. Filed Nov.23, 1970, Ser. No. 92,296 Int. Cl. C07d 31/36 US. Cl. 260-295.5 R 2Claims ABSTRACT OF THE DISCLOSURE 6 halo-2-hydroxynicotinic acid,4amino-2-hydroxynicotinic acid, 2-hydroxy-4-(lower alkyl)nicotinic acid,2- hydroxy-S-(lower alkyl)nicotinic acid, S-halo-Z-hydroxynicotinicacid, and their salts, useful as hypolipidemic agents, are described.

BACKGROUND OF THE INVENTION While it has been known that nicotinic acidis an effective hypolipidemic agent [Miller, 0. N. and Hamilton, I. G.,in R. Paoletti (editor), Lipid Pharmacology, Academic Press, New York,1964, p. 27-6] and is of value in lowering serum cholesterol and lipidlevels in man [Parsons, W. B., Circulation 24, 1099 (1961)], it is alsoknown that its use is beset with side effects, such as vasodilation.Such side effects are highly undesirable since hypolipidemic agentsunder normal conditions are employed over extended periods of time. Thecompounds of the invention are significantly more effectivehypolipidemic agents than nicotinic acid, and therefore can beadministered in such doses as to avoid undesirable side effects.

BRIEF SUMMARY OF THE INVENTION The invention relates tohypolipidemically effective compounds selected from the group consistingof 6-halo- 2-hydroxynicotinic acid, 4-amino-2-hydroxynicotinic acid,Z-hydroxy 4 (lower alkyl)nicotinic acid, Z-hydroxy-S- (loweralkyl)nicotinic acid and S-hal-o-Z-hydroxynicotinic acid, and saltsthereof formed with pharmaceutically acceptable bases.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to novelcompounds selected from the group consisting of6-halo-2-hydroxynicotinic acid, 4- amino-Z-hydroxynicotinic acid,2-hydroxy-4-(lower alkyl)nicotinic acid, 2-hydroxy-5-(loweralkyl)nicotinic acid and S-halo-Z-hydroxynicotinic acid, and saltsthereof with pharmaceutically acceptable bases.

As used herein, the term lower alkyl denotes an alkyl group having from1-4 carbon atoms; methyl is preferred. The term halogen or halo denoteschlorine, bromine, fluorine and iodine; chlorine is preferred.

Preferred compounds of the invention are 6-chloro-2- hydroxynicotinicacid and S-chloro-2-hydroxynicotinic acid.

The compounds of the invention, exemplary of which are6-chloro-Z-hydroxynicotinic acid, 4 amino-2-hydroxynicotinic acid,2-hydroxy-4-methylnicotinic acid, 2-hydroxy-S-methylnicotinic acid and-chloro-2-hydroxynicotinic acid, can be prepared as hereinafterdescribed. For example, a 2-hydroxy-4-(lower alkyl)nicotinic acid can beprepared by treating 4-chloro-2-hydroxynicotinic acid with lower alkyllithium or lower alkyl magnesium bromide; 4-amino-2-hydroxynicotinicacid can be pre- 3,738,990 Patented June 12, 1973 pared by treatingZ-hydroxy-3-methylpyridine with an oxidizing agent to yield thecorresponding N-oxide, treating the N-oxide with nitric acid/sulfuricacid to yield 2-hydroxy-3-methyl-4-nitropyridine N-oxide, oxidizing thelatter N-oxide to yield 2-hydroxy-4-nitronicotinic acid N-oxide, andhydrogenating the latter reaction product to yield the desired4-amino-2-hydroxynicotinic acid; a 6-halo-2-hydroxynicotinic acid can beprepared by treating 2,6-dihalonicotinic acid with a base, for example,an alkali metal hydroxide, such as sodium hydroxide, at the refluxtemperature of the reaction mixture, acidifying the reaction mixturewith an acid, for example, a hydrohalic acid such as hydrochloric acid,and thereafter, recovering the desired end product; a 2-hydroxy-5-(loweralkyl) nicotinic acid can be prepared by treating 2-hydroxy-3-bromo-S-(lower alkyl)pyridine with n-butyl lithium in an inert solvent,for example, tetrahydrofuran, and recovering the desired end product;and a 5-halo-2-hydroxynicotinic acid can be prepared, for example, bytreating 2-hydroxy-5-aminonicotinic acid with sodium nitrite,hydrochloric acid/cuprous chloride or hydrobromic acid/ cuprous bromide,preferably at a temperature below 0 C., and thereafter recovering thedesired end product.

The invention also relates to the salts of the nicotinic acidderivatives hereinbefore discussed, which can be prepared by reactionWith a base having a non-toxic, pharmaceutically acceptable cation.Thus, any base which Will form a salt with a carboxylic acid and whichwill not be toxic or have adverse pharmacological effects can beutilized. Exemplary of such bases are the alkali metal and alkalineearth metal hydroxide carbonates and the like, for instance, sodiumhydroxide, potassium hydroxide, calcium hydroxide, calcium carbonates,and the like, ammonia, primary, secondary and tertiary amines, such asmono-, dior trialkylamines, for instance, methylamine, dimethylamine,trimethylamine, and the like, and nitrogen containing heterocyclicamines, for instance, piperidine and the like.

A respected segment of the scientific community concerned with theproblem of atherosclerosis subscribed to the concept that cholesteroland other lipids play a role in the development of atherosclerosis, afatty degeneration of the inner coat of the arteries; and, sincecholesterol and various other lipids are synthesized by various of thebody organs, compounds which inhibit the synthesis and/or reduce theserum levels of cholesterol and other lipids are considered to beeffective in preventing the development of atherosclerosis.Unexpectedly, it has been discovered that certain derivatives ofnicotinic acid, as herein described, are highly effective hypolipidemicagents.

Thus, the compounds of the invention and their salts formed withpharmaceutically acceptable bases can be utilized in the form ofpharmaceutical preparations for the treatment and prevention ofatherosclerosis.

For such use, the presently disclosed compounds are formulated, usingconventional inert pharmaceutical adjuvant materials, into dosage formswhich are suitable for oral or parenteral administration. Such dosageforms include tablets, suspensions, solutions, and the like.Furthermore, the compounds of this invention can be incorporated into,and administered in the form of, suitable hard or soft capsules. Theidentity of the inert adjuvant materials which are used in formulatingthe present compounds into oral and parenteral dosage forms will beimmediately apparent to persons skilled in the art. These adjuvantmaterials, either inorganic or organic in nature, include for example,water, gelatin, lactose, starch, magnesium stearate, talc, vegetableoils, gums, polyalkylene glycols, and the like. Moreover, preservatives,stabilizers, wetting agents, emulsifying agents, salts for alteringosmotic pressure, buffers, and the like, can be incorporated, ifdesired, into such formulations.

The quantity of active medicament which is present in any of theabove-described dosage forms is variable. It is preferred, however, toprovide capsules or tablets containing from about mg. to about 100 mg.of a compound of the invention or an equivalent amount of apharmaceutically acceptable salt thereof formed with a base. Forparenteral administration, it is preferred, for example, with6-chloro-2-hydroxynicotinic acid, to provide a solution containing fromabout 0.5 mg./ml. to about 5.0 mg./ml. of said compound, or anequivalent amount of a pharmaceutically acceptable salt thereof formedwith a base.

The frequency with which any such dosage form will be administered to awarm-blooded animal will vary, depending upon the quantity of activemedicament present therein and the needs and requirements of thepatient, as diagnosed by the prescriber. Under ordinary circumstances,however, from about 0.25 mg./kg. to about 2.5 mg./kg. of a compound ofthe invention can be administered daily in divided doses. A suitableregimen, for example, with 6-chloro-2-hydroxynicotinic acid comprises 10mg. three times a day. It is to be understood, however, that the dosagesset forth herein are exemplary only and that they do not, to any extent,limit the scope or practice of this invention.

The following examples further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 6-chloro-2-hydroxynicotinic acid A mixture of6.00 g. of 2,6-dichloronicotinic acid and 78 ml. of 2 N NaOH solutionwas refluxed for 2 hours, cooled and acidified with 17 ml. of 10 N HCl.The mixture was cooled 30 minutes in an ice bath, and the solid wasfiltered and washed with water. The solid was slurried in 25 ml. of warmethanol, filtered and washed with Warm ethanol. The ethanol insolublesolid M.P. 296298 dec. was recrystallized from 1500 ml. of 1:2 vol.:vol.ethanolzwater to give 2-chloro-6-hydroxynicotinic acid, having a meltingpoint of 300302 dec. The ethanol filtrate from the solid, having amelting point of 296-298 dec., was let evaporate to dryness and thesolid was slurried in ether, filtered, washed with ether andrecrystallized from 20 ml. of ethanol to give6-chloro-2-hydroxynicotinic acid, having a melting point of 218220 C.dec.

EXAMPLE 2 Preparation of Z-hydroxy-S-methyl-nicotonic acid Method A: Asolution of 5.0 g. of 2-hydroxy-3-bromo- S-methylpyridine in 75 ml. oftetrahydrofuran plus 50 ml. of ether was added dropwise over minutes toa stirred solution of 5.8 g. of n-butyl-lithium in 50 ml. oftetrahydrofuran plus 70 ml. of pentane. The temperature rose to 40. Themixture was stirred for 10 minutes, cooled to and CO bubbled in for 10minutes. The mixture was decomposed with water and dilute hydrochloricacid. The aqueous phase was concentrated to a small volume, chilled andthe crude product which formed was crystallized from ethanol to give2-hydroxy-5-methylnicotinic acid, having a melting point of 270-271 C.

Method B: A mixture of 114 g. of 2-amino-3-bromo-5- methylpyridine, 73g. of cuprous cyanide and 570 ml. of dimethylformamide was refluxed for3.5 hours. The hot reaction mixture was poured into 6 l. of Water,whereupon a tan solid formed. This was filtered, washed with water, andstirred for 10 minutes with 2 l. of concentrated ammonium hydroxide. Theresulting mixture was extracted with 3 l. of chloroform and the CHClevaporated to give 84 g. of solid. This was recrystallized from 1400 ml.of boiling water to give 30 g. of 2-amino-3- cyano-S-methylpyridine,having a melting point of 159- 162". (A second crystallization of asample raised the melting point to 162163.) Thirty grams of 2-amino-3-cyano-5-methylpyridine was dissolved in a warm solution of 700 ml. ofwater plus 70 ml. of concentrated H 50 Ice was added to bring the volumeto 1 l. and the temperature to 30. With stirring, a solution of 56 g. ofNaNO- in 150 ml. of water was added over a period of 10 minutes andsolids were formed. The mixture was stirred for an additional 10 minutesat 30-35", heated to 70 over 15 minutes, and cooled thoroughly in an icebath. The 2 hydroxy-3-cyano-5-methylpyridine. was filtered, washed withwater and dried; wt. 18.9 g., having a melting point of 231-233.(Crystallization of a sample from water raised the melting point to223-235.) To a suspension of 18.9 g. of2-hydroxy-3-cyano-5-methylpyridine in 130 ml. of water was added 130 ml.of concentrated H 50 and the resulting solution was refluxed for 2.5hours. The solution was cooled, treated with concentrated NH to pH 3,and thoroughly cooled. The solid was filtered, washed with water, airdried and crystallized from 2.5 l. of boiling ethanol (charcoal) to givecolorless platelets of 2-hydroxy-5-methyl-nicotinic acid, having amelting point of 270-271, having an identical IR spectrum when comparedwith material made by Method A.

EXAMPLE 3 Preparation of 5-chloro-Z-hydroxynicotinic acid A slurry of24.7 g. of 2-hydroxy-5-aminonicotinic acid in 111 ml. of concentratedhydrochloric acid was stirred, cooled to 5 and a solution of 16.2 g. ofNaNO;,, in 40 m1. of water was added dropwise over a period of 15minutes, maintaining the reaction temperature in the range of -5 to 2'.The slurry was stirred at 5 for a further 15 minutes and was then pouredslowly over a period of 10 minutes into a stirred solution of 18,8 g. ofcuprous chloride in ml. of concentrated HCl cooled to 5, maintaining thetemperature at 5 to 15. The slurry was then stirred at room temperaturefor 2.5 hours, and the solid was filtered, washed with two times 20 ml.of water and then with 20 ml. of ethanol and dried. The crude productwas recrystallized first from ethanol and then from water to give yellowneedles of 5-chloro-2-hydroxynicotinic acid, having a melting point of266-268.

EXAMPLE 4 Tablet formulation Per tablet, mg.

(1) 2-hydroxy-5-methylnicotinie acid, lactose, corn starch, andprehydrolyzed corn starch are blended in a suitable mixer.

(2) The mixture is granulated to a heavy paste with water and the moistmass is passed through a No. 12 screen, and dried overnight at F.

(3) The dried granules are passed through a No. 16 screen andtransferred to a suitable mixer. The calcium stearate is added and mixeduntil uniform.

(4) The mixture is compressed at a tablet weight of 410 mg. using tabletpunches having a diameter of approximately (Tablets may be either flator biconvex and may be scored if desired.)

EXAMPLE 5 Tablet formulation Per tablet, mg.

Procedure (1) 6-chloro-Z-hydroxynicotinic acid, lactose, corn starchandpregelatinized corn starch are mixed in a suitable mixer.

(2) The mix is passed through a Fitzpatrick Comminuting Machine fittedwith No. 1A screen, with knives forward.

(3) The mixture is returned to the mixer and moistened with water to athick paste. The moist mass is passed through a No. 12 screen, and themoist granules are dried on paper-lined trays at 110 F.

(4) The dried granules are returned to the mixer, and

the calcium stearate is added and mixed well.

(5) The granules are compressed at a tablet weight of 200 mg. usingstandard concave punches having a diameter of A EXAMPLE 6 Capsuleformulation Per capsule, mg.

6-chloro-2-hydroxynicotinic acid 25.5 Lactose 159.5 Corn starch 30.0Talc 5.0

Total weight 220.0

Procedure:

6 EXAMPLE 7 Parenteral formulation Each 1 cc. ampul contains: Per cc.6-chloro-2-hydroxynicotinic acid mg 5.1 Methyl paraben, USP mg 1.8Propyl paraben, USP mg 0.2

Hydrochloric acid, p.s. pH 4.5. Water for injection, q.s., add 1 cc.

1 2% excess.

Procedure (for 10,000 cc.):

( 1) In a clean glass or glass-lined vessel, 8,000 cc. of Water forInjection are heated to C., then cooled to 50-60" C. 18 grams of methylparaben and 2 grams of propyl paraben are added and dissolved withstirring. The solution is then allowed to cool to room temperature.

(2) The 51.0 grams of 6-chloro-2-hydroxynicotinic acid are added underan atmosphere of nitrogen and stirred until completely dissolved.

(3) The hydrochloric acid is added as 1 N solution until the pH isadjusted to 4.5 plus or minus 0.2.

(4) Suflicient Water for Injection is added to make a total volume of10,000 cc.

(5 This solution is filtered through an .02 Selas candle, filled intosuitable size ampuls, gassed with nitrogen and sealed. The ampuls areautoclaved at 10 lbs. p.s.i. for 30 minutes.

We claim:

1. A compound selected from the group consisting of6-halo-2-hydroxynicotinic acid, and salts thereof formed withpharmaceutically acceptable bases.

2. A compound in accordance with claim 1, 6-chloro-2- hydroxynicotinicacid.

References Cited Spath et al., Chem. Abstracts, vol. 18, p. 1500 (1924).

Dornow et al., Chem. Abstracts, vol. 45, 9052 (1951).

Kochetkov et al., Chem. Abstracts, vol. 47, 3309 (1953).

Dornow et al., Chem. Abstracts, vol. 52, 2016g to 2017d (1958).

Guarneri et al., Chem. Abstracts, vol. 56, 12,847i to 12,849d (1962).

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R. 424--266

